Levels of MHC class I gene expression are altered by a variety of stimuli. Agents such as TNF and interferon are well known induced of class I transcription, many other factors also affect expression. We have shown that thyroid stimulating hormone (TSH) specifically reduces transcription of class I genes; this down-regulation is cAMP mediated. Three DNA elements have been shown to be targets of cAMP action: a classical CRE, a PKA-responsive element (PKARE), and the promoter itself. These three elements appear to interact to transduce the cAMP signal. Analysis of cell extracts from normal and TSH-thyrocytes reveals THS-mediated differences in factors binding to the CRE and PKARE. Other agents are capable of modulating class I expression in thyrocytes. Among them, insulin, hydrocortisone, methimazole, and serum act as negative regulators. The DNA elements responsive to thyroid hormone and hydrocortisone map to a segment between -135 bp and -209 bp, a region known to contain both the IFN-response element and enhancer A. Hydrocortisone has been shown to reduce the association of a complex of Fra2 and the p50 subunit of NfkappaB with enhancer A. Methimazole has been shown to target both an upstream complex regulatory element and the downstream CRE. The methimazole- mediated decrease in class I transcription depends on the presence of insulin. DNA binding factors induced by methimazole that bind to the class I elements also bind to insulin-response elements of TSHr and thyroglobulin genes.